Derivatives of sequence-specific oligodeoxyribonucleoside methylphosphonates will be prepared in which a trimethylpsoralen, bromoacetamide or ethylenediamine tetraacetate group is linked to the oligomer. The oligomers which can be taken up intact by mammalian cells in culture are designed to selectively crosslink with or hydrolyze a complementary target nucleic acid. By this means the oligomers can be used to regulate gene expression at the mRNA translation or splicing level or at the level of DNA transcription or replication. The effect of the oligomers on gene expression will be tested in four systems: (a) Derivatized oligomers complementary to selected regions of rabbit Alpha or Beta globin mRNA will be tested for their ability to crosslink with or cleave their target mRNA and to selectively inhibit mRNA translation in a cell-free system; (b) Oligomers complementary to the initiation codon regions of Vesicular stomatitis virus mRNA will be tested for their ability to inhibit translation of VSV mRNA in a cell-free translating system and in VSV-infected cells; (c) Oligomers complementary to the splice junctions of SV40 large T-antigen precursor mRNA will be tested for their ability to prevent T-antigen production in SV40-infected African green monkey kidney cells and splicing of T-antigen pre-mRNA: (d) Oligomers complementary to part of the origin of replication of SV40 will be tested for their ability to inhibit DNA transcription and/or replication in SV40-infected cells. The long range objective of this research project is to develop oligonucleotide reagents which can be used by virologists and molecular biologists to study virus and cellular gene expression in cell culture systems.